6-aryl pyrimidines for treating aplastic anemia

ABSTRACT

A method for treating aplastic anemia by systemic administration of a 6-aryl pyrimidine compound or a pharmaceutically acceptable salt thereof in association with a pharmaceutical carrier to a human or animal having aplastic anemia.

This application is a continuation of application Ser. No. 281,820,filed July 9, 1981, now abandoned, which is a continuation ofapplication Ser. No. 136,436, filed Apr. 20, 1980, now abandoned, whichis a division of application Ser. No. 079,850, filed Sept. 28, 1979, nowabandoned.

DESCRIPTION BACKGROUND OF THE INVENTION

The preparation and use of 2-amino-5-halo-6-alkyl-4-pyrimidinols asantiviral agents is known (U.S. Pat. No. 3,956,302 and Nichols, Weed andUnderwood, Antimicrobial Agents and Chemotherapy 9,433, 1976).Preparation of 2-amino-5-bromo-6-phenyl-4-pyrimidinol (V, where X₃ is Brand X₁ is phenyl) has been reported (Brown and Stevens, JCS Perkin I,1023, 1975) but no utility has been described for this material. Snell,Elias and Freeman in GB No. 1,223,686 (1967) disclose a variety of5,6-disubstituted 2-amino-4-pyrimidinols, such as2-dimethylamino-5-bromo-6-methyl-4-pyrimidinol. Various 5-unsubstituted2-amino-6-arylpyrimidinols are known (e.g., Shirahawa, Yakuyaku Fasshi50, 1562, 1960 (CA 55, 10651b); Kulkarui et al., J. Sci. and Ind. Res.Indil, 19C, 6, 1960; and U.S. Pat. No. 2,776,283. Diuretics andcardioregulatory properties are described for various 2-amino and2-substituted amino-5-aminomethyl and 5-aryl-6-aryl-4-pyrimidinols, U.S.Pat. No. 2,704,285, U.S. Pat. No. 2,723,777 and U.S. Pat. No. 2,776,283.

The 2-amino-6-aryl-5-substituted pyrimidinols of this invention havebeen shown to exhibit antiviral activity, an improved therapeutic ratioand fewer side effects and are useful in preventing and treating viralinfections. The antiviral activity of many of the compounds isassociated with increased production of interferon. Other compoundsexhibit antiviral activity but do not induce interferon production.

The 2-amino-6-aryl-5-substituted pyrimidinols of this invention exhibitimmunoregulatory activity of the following types: increased antibodyformation, increase in natural killer cells, activation of macrophages,increase in hematopoietic stem cells and decrease in generation ofallospecific killer cells.

BRIEF DESCRIPTION OF THE INVENTION

This invention relates to 6-aryl pyrimidine compounds which have beenfound to be useful for treatment or prevention of pathologicalconditions related to the immunoregulatory system.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention are prepared from β-keto estercompounds. The starting β-keto esters are prepared as follows.

A four step procedure starting with a compound of the formula Ia whereinZ is alkyl of from 1 to 5 carbon atoms, inclusive, including isomericforms, or ##STR1## wherein R₁₀, R₁₁ and R₁₂ are the same or differentand are alkyl of from 1 to 5 carbon atoms, inclusive, including isomericforms or phenyl; and X and X₁ are as defined above. ##STR2##

Although the reaction sequence is set forth as four steps for clarity,from the chemists point of view the reaction is "one-step" in that thesequence takes place in a single reaction vessel without requirement forseparation and purification after each reaction.

In step 1 the starting material, monoalkyl malonate, preferablymonoethylmalonate Ia (Z=C₂ H₅), is treated in dry solvent with twoequivalents of lithium base at reduced temperature.

Dry solvents can be, for example, tetrahydrofuan, diglyme, glyme,dioxane, hexamethylphosphoric triamide, or dimethylformamide.

By lithium base is meant for example compounds of the formula R₈ -Liwherein R₈ is n-butyl, methyl, phenyl, t-butyl, s-butyl or LiN(R₉)₂wherein R₉ is isopropyl, cyclohexyl, and trimethylsilyl or a combinationthereof. n-Butyl lithium is preferred.

By reduced temperature is meant from 0° C. to -80° C. with a startingtemperature of about -70° C. preferred.

Following the addition of the lithium base, with concommittant rise intemperature, the reaction mixture is recooled to about -65° C. whereuponan acid halide ##STR3## is added (Step 2). The acid halide can be addedeither neat or diluted with dry solvent. Dropwise addition of acidhalide in dry solvent at about -65° C. is preferred.

The optimum ratio of malonate to acid halide is 1.7 (or greater) forhighest yields. Acylation (step 2) and decarboxylation (step 3) toafford Id is hastened by allowing the reaction temperature to warmslowly to room temperature.

Step 4i, or work up procedure, simply involves quenching the reaction athe appropriate time with dilute acid followed by extraction with ether.The organic phase is washed with bicarbonate, dried, and concentrated toyield the desired β-ketoester, IIi.

Alternatively, in step 4ii (X is not hydrogen), at least one equivalentof X-chloride, -bromide, or -iodide (preferably X-bromide or X-iodide)is added at room temperature and the reaction mixture allowed to standuntil the alkylation is complete. If desired, the mixture may be warmedto hasten the alkylation. The mixture is then quenched with dilute acid,extracted with ether and the ether phase washed and concentrated, asdescribed for step 4i, to yield the desired α-substituted β-keto ester,IIii. If desired, IIii may be further purified by conventional methodssuch as chromatography, distillation, and the like.

EXAMPLES EXAMPLE 1 Ethylisobutyryl Acetate

To a 1 liter, 3-necked round-bottom flask, fitted with a nitrogen inletthermometer, and an overhead stirrer is added 19.8 g. (147 mM) ofmonoethylmalonate, 350 ml. of dried THF and 2 mg. of bipyridyl. Thesolution is cooled to -70° C. and a 1.6M solution of n-butyllithium inhexane (Foote Chemicals Co. or Aldrich Chemical Co.) is added, dropwiseat -70° C. to -5° C. until a pink color persisted. The temperature isallowed to slowly rise to -5° C., throughout the butyllithium addition,during which time the pink color formed will dissipate. After the pinkcolor remains for five minutes at -5° C. (approx. 210 ml. ofbutyllithium has been added), the mixture is cooled to -65° C. and 7.9ml. (7.98 g. 75 mM) of isobutyryl chloride is added dropwise at -60° C.to -65° C. The solution is stirred vigorously at -60° C. to -65° C., for5 minutes and poured into 500 ml. of ether +300 ml. of ice-cold 1Nhydrochloric acid. After shaking, the layers are separated and theorganic layer is washed 2×150 ml. saturated aqueous sodium bicarbonate1×150 ml. water and dried over sodium sulfate (anhyd.). The etherealsolution is filtered, the solids washed with ether and the combinedfiltrates evaporated to dryness to yield 11.7 g. (98.4%) ofethylisobutyryl acetate, m.w. 158.19.

NMR (CDCl₃): δ 4.38-4 (q, 2H, O--CH₂ --CH₃), 3.5 ##STR4## 2.96-2.41 (m,1H, CH(CH₃)₂, 1.46-1 (m, 9H, CH₃).

GLPC R.T.=3.2 min (T=90°, 3', 3% OV 17).

GC/MS M+ m/e 159 (27%), 116 (100%).

EXAMPLE 2 Ethyl-n-butyryl Acetate

Following the procedure for the preparation of ethylisobutyryl acetatebut substituting 7.98 g. (75 mM) of n-butyryl chloride in 50 ml. ofdried THF for the 7.9 ml. of isobutyryl chloride, 11.4 g. (96.6%) ofethyl n-butyryl acetate is isolated, m.w. 158.19.

NMR (CDCl₃): δ 4.38-4.0 (q, 2H, OCH₂), 3.43 (s, 2H, COCH₂ CO), 2.65-2.41##STR5## 1-91-0.78 (m, 10H, CH₃ CH₂ CH₂ C, CH₃ CH₂ O)

GLPC R.T.=3.1 min (T=90°, 3', 3% OV 17)

EXAMPLE 3 Ethylpropionyl Acetate

Following the procedure for the preparation of ethylisobutyryl acetatebut substituting 71. g. of monoethylmalonate (0.613M), 1300 ml. of THFand 28.1 g. of propionyl chloride (0.305M) in 300 ml. THF (addeddropwise) to yield 42.0 g. (95.2%) of ethylpropionyl acetate as an oil,m.w. 144.17.

NMR (CDCl₃): δ 4.36-4 (q, 2H, O--CH₂ --CH₃), 3.41 ##STR6## 2.75-2.38 (q,2H, COCH₂), 1.5-0.86 (m, 5H, CH₃).

GLPC R.T.=5.6 min (90°, 6', 3% OV 17).

GC/MS M+ m/e (76.5%), 115 (100%).

EXAMPLE 4 Ethylphenylacetyl Acetate

Following the procedure for the preparation of ethylisobutyryl acetatebut substituting 10.0 ml. (11.69 g. 75 mM) of phenylacetylchloride(Aldrich Chem. Co.) for the 7.9 ml. of isobutyryl chloride gave 15.4 g.(98.8%) of ethyl phenylacetyl acetate, m.w. 206.23.

NMR (CDCl₃): δ 7.38-7.13 (m, 5H, Ar), 4.31-3.95 (q, 2H, OCH₂), 3.78 (s,2H, CH₂), 3.38 ##STR7## 1.33-1.11 (t, 3H, CH₃).

EXAMPLE 5 Ethylbenzoyl Acetate

Following the procedure for the preparation of ethyl-isobutyryl acetatebut substituting 6.06 g. of monoethylmalonate (45 mM), 250 ml. THF and2.64 ml. of benzoylchloride (3.15 g. ≈2.55 mM) and stirring the reactionmixture at -65° for 60 minutes gave 4.18 g. (97%) of ethylbenzoylacetate as an oil, m.w. 192.21. This material was isolated as a mixtureof tautomers (H'-NMR).

NMR (CDCl₃): δ 8.06-7.25 (m, 5H, Ar), 5.66 ##STR8## 4.43-3.96 (m, 3.9H,OCH₂ CH₃, COCH₂ CO), 1.45-1.11 (m, 3H, CH₃).

GLPC R.T.=3.1 min (85°, 60 cm, UCW-98-2).

GC/MS M+ m/e 192 (6.8%), 105 (100%).

EXAMPLE 6 Ethyltoluoyl Acetate

Following the procedure for the preparation of ethyl benzoyl aceatatebut substituting 15.5 g. of monoethylmalonate (115 mM), 500 ml. THF and11.1 g. (71.8 mM) of toluoyl chloride gave 13.44 g. (90.8%) of ethyltoluoyl acetate as an oil. H'-NMR indicates the desired product is amixture of tautomers, m.w. 206.23.

NMR (CDCl₃): δ 8.05-7.61 (m, 2H, 2,6-ArH), 7.41-7.13 (m, 2H, 3,5-ArH)5.63 ##STR9## 4.41-4.03 (m, 2H, CH₂ CH₃), 3.95 ##STR10## 2.4 (s, 3H,ArCH₃), 1.43-1.11 (m, 3H, CH₂ CH₃).

EXAMPLE 7 Ethylanisoyl Acetate

Following the procedure for the preparation of ethylbenzoyl acetate butsubstituting 15.5 g. of monoethyl malonate (115 mM), 400 ml. of THF and12.24 g. (71.8 mM) of anisoyl chloride gave 14.45 g. (90.3%) ofethylanisoyl acetate as an oil, m.w. 222.23.

NMR (CDCl₃): δ 8.03-7.86 (m, 2H, 2,6-ArH), 7.08-6.86 (m, 2H, 3,5-ArH),4.38-3.85 (m, 7H, OCH₃, COCH₂ CO, OCH₂ CH₃), 1.36-1.13 (t, 3H, CH₂ CH₃).

EXAMPLE 8 Ethyl-p-Chlorobenzoyl Acetate

Following the procedure for the preparation of ethylbenzoyl acetate butsubstituting 15.5 g. of monoethylmalonate (115 mM), 400 ml. THF and 12.5g. (71.5 mM) of p-chlorobenzoyl chloride gave 15.56 g. (95.6%) of ethylp-chlorobenzoyl acetate as a solid. Recrystallization of an analyticalsample from methanol gave solid ethyl-p-chlorobenzoyl acetate as amixture of tautomers, m.w. 226.65.

NMR (CDCl₃): δ 7.95-7.21 (m, 4H-ArH), 5.61 ##STR11## 4.41-1 (m, 2H, CH₂CH₃), 3.9 (s, 1.36H, COCH₂ CO), 1.43-1.1 (m, 3H, CH₂ CH₃).

Analysis: Calc'd. for C₁₁ H₁₁ ClO₃ : C, 58.28; H, 4.89; Cl, 15.64.Found: C, 58.34; H, 5.13; Cl, 15.32.

EXAMPLE 9 Ethyl 3,4-Dichlorobenzoyl Acetate

Following the procedure for the preparation of ethyl benzoyl acetate butsubstituting 15.5 g. (115 mM) of monoethylmalonate, 400 ml. of THF, and12.0 g. (57.5 mM) 3,4-dichlorobenzoyl chloride gave 14.56 g. (97%) ofethyl 3,4-dichlorobenzoyl acetate. This material slowly crystallized onstanding at -12° C. and was isolated as a mixture of tautomers, m.w.261.1.

NMR (CDCl₃): δ 8.06-7.5 (m, 3H, ArH), 5.63 ##STR12## 4.4-4.03 (m, 2H,CH₂ CH₃), 3.93 (s, 1.42H, COCH₂ CO), 1.46-1.13 (m, 3H, CH₂ CH₃).

Analysis:

Calc'd. for C₁₁ H₁₀ Cl₂ O₃ : C, 50.59; H, 3.86. Found: C, 50.21, H,4.79.

EXAMPLE 10 Ethyl-α-ethyl-benzoylacetate

To 13.2 g. of monoethylmalonate was added 300 ml. THF and 5 mg. ofbipyridyl. Butyl lithium was added at -70° C. to -10° C. until a pinkcolor persisted. The reaction mixture was recooled to -70° C. and 6.4ml. of benzoyl chloride (0.06M) was added. After stirring at -60° C. for60 minutes, 28.2 g. (0.182M) of ethyl idodide was added and the reactionmixture allowed to stir, at ambient temperature, for 18 hours. Themixture was then warmed to 50° C. and kept at 50° C. for 90 hours. Atthis time the entire mixture was poured into 500 ml. diethyl ether+300ml. 1N hydrochloric acid, the layers separated, and the organic layerwashed one time 1N hydrochloric acid, once in saturated aqueous sodiumbicarbonate and once with water. Drying over sodium sulfate (anhyd.),filtering and evaporating yielded 13.6 g. of ethylα-ethyl-benzoylacetate as an oil.

NMR: 8.11-7.91 (m, 2H, φ), 7.66-7.30 (m, 3H, φ), 4.35-3.96 (m, 3H,COCHCO, OCH₂ CH₃), 2.30-1.80 (m, 2H, CH₂ CH₃), 1.43-0.76 (m, 6H, CH₃).

The novel compounds of this invention are represented by the formula:##STR13##

The compounds can exist in tautomer form and can be depicted as follows:##STR14## Thus they can be named as pyrimidinols or pyrimidinones.

The pyrimidine compounds can also be named as isocytosines, e.g,2-amino-5-bromo-6-m-fluorophenyl-4-pyrimidinol can also be named5-bromo-6-m-fluorophenyl isocytosine.

The novel pyrimidines (V) can be prepared according to the followingmanner from the previously described β-keto esters: ##STR15## Thecondensation of the appropriate β-keto ester IIii with guanidine (III)can be carried out in polar solvents such as ethanol, isopropanol,1-butanol, dimethylformamide (DMF), and the like, with ethanolpreferred, in the presence of a base such as a carbonate (for example,sodium carbonate or guanidium carbonate itself) or an alkoxide (such assodium ethoxide) and the like, under reflux in the usual manner. Theproduct V (wherein X₃ is X₁ or X₅) is isolated by neutralization withacid or carbon dioxide of the reaction mixture after condensation iscomplete as determined by TLC, and filtration or chromatography in theconventional manner.

The preparation of V (wherein X₃ is X₄) is carried out from anappropriate β-keto ester IIi and guanidine (III) as described above toyield IV in like manner. Subsequent halogenation of IV for example bytreatment with N-chlorosuccinimide in acetic acid to yield V wherein X₃=X₄ =Cl, or for example by treatment with bromine in acetic acid toyield V wherein X₃ =X₄ =Br, or for example by treatment with anequivalent of 1N sodium hydroxide followed by iodine in chloroform toyield V wherein X₃ =X₄ =I, can be carried out to afford the novelpyrimidines V wherein X₃ =X₄. Alternative methods of halogenation areillustrated in the following procedures. The final pyrimidines can beisolated by concentration in vacuo and aqueous trituration of theresidue followed by filtration of the resultant solid.

EXAMPLE 11

General procedure and preparation of pyrimidines of the formula:##STR16##

The compounds prepared and the procedure used are shown in Table 1.

PROCEDURE 1 Condensation to IV or V (X₃ =X or X₅)

To 20 mM of powdered quanidine carbonate was added, under nitrogen, 120ml. of absolute ethanol and 20 ml. of toluene. The reaction mixture washeated to reflux and 50 ml. of solvent was distilled off. The mixturewas cooled to 45° C. and 40 mM of β-ketoester (II or IIii) added. Thismixture was heated to reflux, with stirring, until the reaction appearedcomplete by TLC. Water (50 ml.) was added and the refluxing continuedfor an additional 30 minutes, at which time the reaction mixture wascooled to 20° C. and neutralized by addition of dry carbon dioxide or 1Naqueous hydrochloric acid. The mixture was allowed to cool at 5° C. for18 hours, filtered and the resulting precipitate washed well with waterfollowed by diethyl ether. The solids were dried at 60° C. under vacuumto yield the desired pyrimidine as a white solid. If the crude solidswere not analytically pure they could be recrystallized from appropriatesolvents, such as aqueous DMF, aqueous ethanol, and the like.

PROCEDURE 2 Condensation

The reaction was carried out exactly as described in Procedure 1,except, after neutralization (addition of carbon dioxide or 1Nhydrochloric acid) the aqueous mixture was evaporated to dryness undervacuum and 100 ml. of water and 100 ml. ethyl ether were added. Themixture was shaken and allowed to sit at 5° C. for 18 hours. The mixturewas filtered and solids washed well with water followed by ethyl ether.Drying and crystallization as described in Procedure 1 gave analyticallypure pyrimidine.

PROCEDURE 3 Bromination (wherein X₃ =Br)

To 15 mM of the appropriate pyrimidine was added 80 ml. of glacialacetic acid. The reaction mixture was warmed to 50° C. to affectsolution (if solids were in solution at 22° C., then it was notnecessary to warm) and 0.81 ml. of Br₂ was added. The solution wasallowed to stir at ambient temperature for 3 hours. The reaction wasevaporated to dryness, under vacuum, and, to the resulting solids wasadded 150 ml. of hot water. The slurry was heated to reflux and allowedto cool to 22° C. The solids were filtered and washed well with water.The solids were pulverized and reheated with 150 ml. of water asdescribed previously. This procedure was repeated. The pyrimidine wasdried in a vacuum oven at 60° C. to give analytically pure material. Ifdesired, it can be recrystallized from water:DMF by adding DMF slowly toa stirring slurry of compound in 150 ml. of boiling water until solutionoccurs. Cooling and filtering yielded analytically pure material.

PROCEDURE 4 Bromination (wherein X₃ =Br)

To 15 mM of the appropriate pyrimidine was added 50 ml. of water and0.66 g. of NaOH (16.5 mM). The solution was allowed to stir at ambienttemperature for 30 minutes and 0.9 ml. of Br₂ (22.62 g. 16.5 mM) in 50ml. of chloroform was added. The reaction mixture was stirred,vigorously, for 2 hours and filtered. Solids were washed well withwater, followed by water and dried at 60° C. in a vacuum oven for 18hours. Recrystallization from water:DMF as per Procedure 3 gaveanalytically pure material.

PROCEDURE 5 Iodination (wherein X₃ =I)

To 15 mM of the appropriate pyrimidine was added 50 ml. of water and0.80 g. (20 mM) of sodium hydroxide. The mixture was stirred and heatedto 50° C. until solution occurred. A slurry of 3.79 g. of powdered I₂(15 mM) in 100 ml. of chloroform was added. The excess I₂ was washedinto the reaction vessel with an additional 30 ml. of chloroform. Themixture was allowed to stir, vigorously, at ambient temperature for fourhours.

The solids were filtered, washed well with water (until water wasneutral to pH paper) followed by either acetone or ethyl acetate untilthe organic wash was colorless. It is often desirable to pulverize thesolids before washing. The solids were dried at 60° C. in a vacuum oven.If material is not analytically pure it may be recrystallized fromwater:DMF by adding DMF slowly to a vigorously stirring slurry of thepyrimidine in 150 ml. of boiling water until solution occurs. Cooling,filtering and drying at 60° C. gives analytically pure material.

PROCEDURE 6 Iodination (X₃ =I)

To 1.95 mM of appropriate pyrimidine was added 25.0 ml. of glacialacetic acid and 434 mg. (2 mM) of N-iodosuccinimide. The reactionmixture was allowed to stir at ambient temperature for 5 days. Themixture was evaporated to dryness under vacuum at 50° C. The solids werepurified by heating with 50 ml. of absolute ethanol at reflux andcooling to room temperature. Filtering and washing with absolute ethanolgave the pure 5-iodopyrimidine.

PROCEDURE 7 Chlorination (X₃ =Cl)

To 0.1M of a 6-arylpyrimidine was added 500 ml. of glacial acetic acidand 14.6 g. of N-chlorosuccinimide (0.11M). The reaction mixture washeated on a steam bath for 11/2 hours. The reaction mixture was cooledto 22° C., evaporated to a volume of 200 ml. and filtered. The solidsthus obtained were washed with glacial acetic acid followed by ethylether and dried at 60° C. in a vacuum oven. If the solids are notanalytically pure, they can be recrystallized from water:DMF by addingDMF to a boiling slurry of the pyrimidine in 500 ml. water untilsolution occurred. Cooling and filtering gives an analytically pure5-chloro-6-arylpyrimidine.

PROCEDURE 8 Fluorination (X₃ =F)

The introduction of fluorine into the 5-position of the pyrimidine ringis effected by fluorination of IV with trifluoromethylhypofluoritefollowed by base according to the procedure of M. J. Robbins and S. R.Naik, J. Am. Chem. Soc. 93, 5277 (1971). Alternatively, if desired, IVmay be fluorinated directly with fluorine-pyridine complex to produce Vwhere X₃ =F by the procedure described by H. Meinert and D. Cech, Z.Chem. 12, 292 (1972).

PROCEDURE 9 Preparation of V (X₃ =CF₃)

Preparation of V wherein X₃ =CF₃ may be achieved starting with V whereinX₃ =I by the exchange procedures described by D. Cech, R. Wohlfeil andG. Efzold, Nucleic Acids Research 2, 2183 (1975) and by Y. Kobayashi, I.Kumadaki and F. Yamamato J.C.S. Chem. Comm. 536 (1977) usingtrifluoromethyliodide and copper-bronze. In like manner,5-perfluoroalkylpyrimidines (V, X₃ =perfluoroalkyl) may be preparedusing perfluoroalkyl iodides.

Alternatively, if desired, the trifluoromethyl or perfluoroalkyl groupcan be introduced earlier at the β-ketoester stage and the resultingtrifluoromethyl or perfluoroalkyl β-ketoester condensed with guanidineas in Procedures 1 or 2 to produce V (X₃ =CF₃ or perfluoroalkyl).Preparation of a trifluoromethyl or perfluoromethyl, β-ketoester may beachieved by methods known in the art. For example, condensation of##STR17## and CH₂ ═CF₂ in the presence of SbF₅ affords ##STR18## andcarboalkoxylation under standard conditions yields ##STR19##

PROCEDURE 10 Preparation of V (X₃ =CH₂ --X₄)

Preparation of V wherein X₃ =CH₂ X₄ can be accomplished under standardconditions known in the art from the corresponding hydroxymethyl (V,wherein X₃ =CH₂ OH) intermediates. These intermediates can be preparedunder standard conditions from IV and formaldehyde or alternatively froma suitably protected β-ketoester, for example ArCOCH(CH₂ OCH₂ φ)CO₂ Et,itself prepared from I by the previously described chemistry wherein Xis --CH₂ OCH₂ φ. Hydrogenylitic or protolytic removal of the benzylgroup will yield V wherein X₃ =CH₂ OH, after condensation of theβ-ketoester with guanidine as described in Procedure 1. The resulting5-hydroxymethylpyrimidine is transformed into the corresponding5-halomethylpyrimidine by standard procedures known in the art, eithervia displacement reactions on the corresponding 5-tosyloxymethylderivative (formed with toluensulfonyl chloride in pyridine) with alkalior alkaline earth halogen salts, or directly with the knownphosphine--carbon tetrahalide methodology.

    __________________________________________________________________________                      Pro-                                                                          ce-                                                                           dure                                                                             CALCULATED           FOUND                               X.sub.0  X.sub.1  No..sup.a                                                                        C  H  N  F  Cl Br I  C  H  N  F  Cl Br I                 __________________________________________________________________________                                              m.p., other.sup.b                   Cl       φ    7  54.19                                                                            3.63                                                                             18.95 15.99    54.64                                                                            3.75                                                                             19.15 15.38                   Br       φ    3  45.13                                                                            3.03                                                                             15.79    30.03 45.20                                                                            3.00                                                                             15.66    29.92                I        φ    5  38.36                                                                            2.57                                                                             13.42       40.53                                                                            38.46                                                                            2.57                                                                             13.28       39.74             CH.sub.3 φ    1  65.65                                                                            5.51                                                                             20.88          65.52                                                                            5.38                                                                             20.86                         Br       4-CH.sub.3 φ.HBr                                                                   3  36.59                                                                            2.79                                                                             11.63    44.27 37.48                                                                            3.18                                                                             12.01    43.36                I        4-CH.sub.3 φ                                                                       5  40.38                                                                            3.08                                                                             12.84       38.80                                                                            40.32                                                                            3.19                                                                             12.93       38.14             Br       4-Cl φ                                                                             3  39.96                                                                            2.34                                                                             13.98 11.79                                                                            26.59 39.92                                                                            2.38                                                                             14.12 10.65                                                                            27.87                Cl       3-F φ                                                                              7  50.12                                                                            2.95                                                                             17.53                                                                            7.93                                                                             14.80    50.16                                                                            2.90                                                                             17.43                                                                            7.84                                                                             14.40                   Br       3-F φ                                                                              3  42.27                                                                            2.48                                                                             14.79                                                                            6.68  28.13 42.24                                                                            2.47                                                                             14.73                                                                            6.74  28.15                I        3-F φ                                                                              5  36.27                                                                            2.13                                                                             12.64                                                                            5.74     38.73                                                                            36.30                                                                            2.18                                                                             12.65                                                                            5.59     38.10             Br       3-Br φ                                                                             3  34.81                                                                            2.04                                                                             12.18    46.32 30.95                                                                            1.89                                                                             11.05    20.54                                                                            32.06             Cl       3-I φ                                                                              7  34.56                                                                            2.03                                                                             12.09 10.20 36.51                                                                            34.55                                                                            1.94                                                                             11.77 10.54 36.2              Br       3-I φ                                                                              3  30.64                                                                            1.80                                                                             10.72    20.39                                                                            32.37                                                                            30.86                                                                            1.94                                                                             10.90    20.10                                                                            32.08             I        3-I φ                                                                              5  27.33                                                                            1.60                                                                              9.57       57.82                                                                            27.58                                                                            1.77                                                                             9.62        56.22             Cl       3-CH.sub.3 O φ                                                                     7  52.58                                                                            3.98                                                                             16.73 13.94    52.22                                                                            3.95                                                                             16.65 13.91                   Br       3-CH.sub.3 O φ                                                                     3  44.59                                                                            3.40                                                                             14.19    26.99 44.22                                                                            3.62                                                                             14.11    26.59                I        3-CH.sub.3 O φ                                                                     5  38.51                                                                            2.94                                                                             12.25       36.98                                                                            38.78                                                                            3.03                                                                             12.16       36.85             Br       3-NO.sub.2 φ                                                                       3  38.61                                                                            2.27                                                                             18.01    25.68 38.71                                                                            2.23                                                                             18.23    25.75                I        3-NO.sub.2 φ                                                                       5  33.54                                                                            1.97                                                                             15.65       35.44                                                                            31.97                                                                            1.91                                                                             14.96       32.57             Br       3-CF.sub.3 φ                                                                       3  39.54                                                                            2.11                                                                             12.57                                                                            17.06 23.92 39.79                                                                            2.02                                                                             12.08                                                                            17.04 24.11                I        3-CF.sub.3 φ                                                                       5  34.66                                                                            1.85                                                                             11.02                                                                            14.95    33.30                                                                            34.65                                                                            1.47                                                                             11.22                                                                            14.87    33.39             H        α-naphthyl                                                                       1  70.87                                                                            4.67                                                                             17.71          70.76                                                                            4.76                                                                             17.49                         Br       α-naphthyl                                                                       3  53.18                                                                            3.19                                                                             13.29    25.27 53.05                                                                            3.24                                                                             12.71    25.23                                                          45.53                                                                            2.87                                                                             19.56 17.33                   Br       2-furyl  4  37.52                                                                            2.35                                                                             16.41    31.20 36.66                                                                            2.41                                                                             16.10    32.39                I        2-furyl  5  31.70                                                                            2.00                                                                             13.87          33.10                                                                            1.94                                                                             14.40                         I        α-naphthyl                                                                       5  46.30                                                                            2.77                                                                             11.57       34.95                                                                            46.54                                                                            2.90                                                                             11.41       34.86             CH.sub.3 α-naphthyl                                                                       1  71.69                                                                            5.21                                                                             16.72          70.91                                                                            5.34                                                                             16.75                         Cl       2-furyl  7  45.40                                                                            2.85                                                                             19.86 16.75                                        I        4-Cl φ                                                                             5  34.56                                                                            2.03                                                                             12.09 10.20 36.52                                                                            35.00                                                                            2.29                                                                             12.46 10.64 35.02             Br       3,4-Cl.sub.2 φ.HBr                                                                 3  28.87                                                                            1.45                                                                             10.10 17.05                                                                            38.43 29.68                                                                            1.77                                                                             10.86 16.64                                                                            38.28                I        3,4-Cl.sub.2 φ                                                                     5  31.44                                                                            1.58                                                                             11.00 18.56 33.22                                                                            31.27                                                                            1.65                                                                             10.99 17.07 35.43             Br       3,5-Cl.sub.2 φ                                                                     3  35.85                                                                            1.80                                                                             12.54 21.17                                                                            23.85 36.07                                                                            1.82                                                                             12.69 20.18                                                                            25.85                I        3,5-Cl.sub.2 φ                                                                     5  31.44                                                                            1.58                                                                             11.00 18.56 33.22                                                                            31.12                                                                            1.50                                                                             10.75 19.20 28.11                                                       m.p., other.sup.b - 260-280-d       Cl       2,5-Cl.sub.2 φ                                                                     7  41.33                                                                            2.08                                                                             14.46 36.61    41.54                                                                            2.18                                                                             14.63 36.50                                                             m.p., other.sup.b - 255-275-d       Br       2,5-Cl.sub.2 φ                                                                     3                                                                                                     m.p., other.sup.b - 180-181         I        2,5-Cl.sub.2 φ                                                                     5  31.44                                                                            1.58                                                                             11.00          31.54                                                                            1.62                                                                             10.98                                                                   m.p., other.sup.b                   Cl       3-Cl φ                                                                             7  46.90                                                                            2.75                                                                             16.41 27.69    46.95                                                                            2.67                                                                             16.54 27.91                   Br       3-Cl φ                                                                             3  39.96                                                                            2.34                                                                             13.98 11.79                                                                            26.59 40.33                                                                            2.40                                                                             14.00 11.62                                                                            26.99                I        3-Cl φ                                                                             5  34.56                                                                            2.03                                                                             12.09 10.20 36.52                                                                            34.80                                                                            2.12                                                                             12.12 9.93  36.46             Br       2-pyridyl.HBr                                                                          3  31.06                                                                            2.32                                                                             16.10    45.93 30.47                                                                            3.00                                                                             16.09    45.51                I        2-pyridyl                                                                              5  34.41                                                                            2.25                                                                             17.84       40.40                                                                            34.49                                                                            2.39                                                                             18.06       40.25             Br       3-pyridyl                                                                              3  40.47                                                                            2.64                                                                             20.99          39.89                                                                            2.66                                                                             21.85                         I        3-pyridyl                                                                              5  34.41                                                                            2.24                                                                             17.84       40.40                                                                            34.83                                                                            2.22                                                                             18.23       40.47             Cl       2-Cl φ                                                                             7  46.90                                                                            2.75                                                                             16.41 27.69    46.75                                                                            2.74                                                                             16.23 27.64                   Br       2-Cl φ                                                                             3  40.00                                                                            2.35                                                                             13.98 11.80                                                                            26.69 49.90                                                                            2.29                                                                             14.10 11.05                                                                            28.07                I        2-Cl φ                                                                             5  34.56                                                                            2.03                                                                             12.09 10.20 35.52                                                                            34.36                                                                            2.09                                                                             12.16 10.75 34.75             Cl       2-CH.sub.3 φ                                                                       7  56.05                                                                            4.27                                                                             17.83    15.04 55.95                                                                            4.03                                                                             17.64    15.01                Br       2-CH.sub.3 φ                                                                       3  47.16                                                                            3.59                                                                             15.00    28.64 47.04                                                                            3.77                                                                             14.81    29.09                I        2-CH.sub.3 φ                                                                       5  40.38                                                                            3.08                                                                             12.84       38.79                                                                            40.10                                                                            3.04                                                                             12.73       39.05             Cl       2-CH.sub.3 O φ                                                                     7  52.49                                                                            4.01                                                                             16.70    14.09 52.56                                                                            4.27                                                                             16.69    13.11                                                          m.p., other.sup.b - 288-289         Br       2-CH.sub.3 O φ                                                                     3  44.61                                                                            3.40                                                                             14.19    26.99 44.91                                                                            3.38                                                                             14.39    26.64                                                          m.p., other.sup.b                   Br       2-F φ                                                                              3  42.27                                                                            2.48                                                                             14.79          42.86                                                                            2.76                                                                             14.47                         I        2-F φ                                                                              5  36.27                                                                            2.13                                                                             12.69                                                                            5.73     38.33                                                                            36.54                                                                            2.14                                                                             12.83                                                                            5.65     38.04             Cl       2-F φ                                                                              7  50.12                                                                            1.94                                                                             17.52 14.79    49.82                                                                            3.00                                                                             17.13 14.48                   I        4-F φ                                                                              5  36.27                                                                            2.13                                                                             12.69                                                                            5.73     38.33                                                                            36.11                                                                            2.15                                                                             12.53                                                                            5.63     38.03             Br       4-F φ                                                                              3  42.47                                                                            2.48                                                                             14.79                                                                            6.68        41.81                                                                            2.53                                                                             14.47                                                                            6.43                       Cl       4-F φ                                                                              7  50.12                                                                            2.94                                                                             17.53 14.79    50.27                                                                            3.15                                                                             17.49 14.77                   C.sub.2 H.sub.5                                                                        4-F φ                                                                              2  61.79                                                                            5.18                                                                             18.01                                                                            8.14        60.37                                                                            5.16                                                                             18.03                                                                            8.07                       C.sub.2 H.sub.5                                                                        2-F φ                                                                              2  61.79                                                                            5.18                                                                             18.01                                                                            8.14        61.59                                                                            5.12                                                                             17.85                                                                            7.94                       Cl       3,4-Cl.sub.2 φ                                                                     7  41.33                                                                            2.07                                                                             14.46 36.31    41.79                                                                            2.21                                                                             14.5  32.59                   Cl       3-NO.sub.2 φ                                                                       7  45.04                                                                            2.64                                                                             21.01          45.11                                                                            2.50                                                                             20.67                         Cl       α-naphthyl                                                                       7  61.88                                                                            3.71                                                                             15.46 13.04    61.08                                                                            3.76                                                                             15.18 12.73                   CH.sub.2 φ                                                                         φ    1  73.62                                                                            5.45                                                                             15.15          73.34                                                                            5.45                                                                             15.17                         CH.sub.3 CH.sub.2 CH.sub.2 --                                                          φ    1  68.09                                                                            6.59                                                                             18.33          67.84                                                                            6.49                                                                             18.33                         CH.sub.2 ═CHCH.sub.2 --                                                            φ    1  68.70                                                                            5.76                                                                             18.49          68.34                                                                            5.78                                                                             18.39                         Br       2-pyrazine                                                                             3  35.84                                                                            2.26                                                                             26.13    29.81 35.24                                                                            2.33                                                                             26.18    29.09                I        2-pyrazine                                                                             5  30.49                                                                            1.92                                                                             22.23       40.28                                                                            30.67                                                                            2.13                                                                             22.34       40.39             Cl       2-pyrazine                                                                             7  42.96                                                                            2.70                                                                             31.32 15.86    43.10                                                                            2.90                                                                             31.41 15.89                                                             m.p., other.sup.b - 280-281         I        2-CH.sub.3 O φ                                                                     5  38.50                                                                            2.94                                                                             12.25       36.98                                                                            39.09                                                                            3.77                                                                             12.81       33.64                                                       m.p., other.sup.b                   Cl       3,5-(CH.sub.3 O).sub.2 φ                                                           7  51.16                                                                            4.29                                                                             14.91 12.58    51.35                                                                            4.18                                                                             14.78 12.84                                                             m.p., other.sup.b - 0.78%                                                     H.sub.2 O                           Br       3,5-(CH.sub.3 O).sub.2 φ                                                           3  44.48                                                                            1.90                                                                             12.88    24.50 43.81                                                                            3.74                                                                             13.08    24.57                                                          m.p., other.sup.b - 0.48%                                                     H.sub.2 O                           I        3,5-(CH.sub.3 O).sub.2 φ                                                           5  38.62                                                                            3.24                                                                             11.26       34.01                                                                            37.26                                                                            3.15                                                                             11.15       34.74                                                       m.p., other.sup.b                   I        3-C.sub.2 H.sub.5 O φ                                                              5  40.35                                                                            3.38                                                                             11.76       35.53                                                                            40.31                                                                            3.23                                                                             12.04       32.22                                                       m.p., other.sup.b - 7.57%                                                     H.sub.2 O                           Cl       3-C.sub.2 H.sub.5 O φ                                                              7  54.24                                                                            4.55                                                                             15.81 13.34    49.77                                                                            4.65                                                                             14.52 12.38                                                             m.p., other.sup.b                   Br       3-n-C.sub.3 H.sub.7 Oφ                                                             3  48.16                                                                            4.35                                                                             12.96    24.65 47.86                                                                            4.30                                                                             12.87 25.33                   I        3-n-C.sub.2 H.sub.7 Oφ                                                             5  42.06                                                                            3.80                                                                             11.32       34.19                                                                            42.41                                                                            3.75                                                                             11.85                                                                            33.50                      Cl       3-n-C.sub.2 H.sub.7 Oφ                                                             7  55.82                                                                            5.04                                                                             15.02 12.68    55.89                                                                            5.22                                                                             14.99                                                                            12.64                      I        3-C.sub.2 H.sub.5 OC.sub.2 H.sub.4 Oφ                                              5  41.90                                                                            4.02                                                                             10.47       31.63                                                                            40.58                                                                            3.96                                                                             10.73    32.69                __________________________________________________________________________     .sup.a In all of the examples where X.sub.3 is halogen, the procedure         number listed refers only to the appropriate halogenation procedure and       presumes Procedure 1 or 2 has already been accomplished.                      .sup.b A majority of the products exhibit melting points that are not         necessarily a distinguishing characteristic of the compound either becaus     of decomposition or greater than 200° and are therefore not listed                                                                              

EXAMPLE 12 2-Amino-6-(2-furyl)-4-pyrimidinol

To a 3-neck, 500 ml. flask fitted with a paddle stirrer, Dean-Starktrap, and a reflux condenser is added 5.76 g. of powdered guanidinecarbonate (31.9 mM, 200 ml. absolute C₂ H₅ OH and 20 ml. toluene. Thesolution is removed azeotropically. The reaction mixture is allowed tocool to 50° C., the Dean-Stark trap removed, and 10.4 g. (64 mM) ofethyl-2-furyl-acetate (57.07 mM) is added. The reaction mixture isheated at reflux for 18 hours; 50 ml. of water is added and heating iscontinued for 30 minutes. The reaction is allowed to cool to 25° C.Chips of carbon dioxide are added until the mixture is neutral and theflask is placed in the refrigerator at 5° C. under vacuum to yield 5.6g. (49%) of pure 2-amino-6-(2-furyl)-4-pyrimidinol.

EXAMPLE 13 2-Amino-6-(m-chlorophenyl)-4-pyrimidinol

To a 3-neck, 500 ml. RB flask fitted with an overhead stirrer,condenser, and Dean-Stark trap under nitrogen is added 5.76 g. (32mmole) of powdered guanidine carbonate, 200 ml. of absolute ethanol and20 ml. of toluene. By heating to reflux 100 ml. of solvent is removedvia the trap following which the solution is cooled to approximately 50°C. and trap removed. Ethyl-m-chlorobenzoyl acetate (14.8 g., 65 mmole)is introduced into the vessel and the reaction is stirred at reflux for17 hours. Approximately 30 ml. of water is added and heating continuedfor 30 minutes. The mixture is then cooled in a refrigerator for 18hours. The precipitate is filtered and washed with ethanol followed byether and dried at 60° C. under vacuum to yield 10.6 g. (74%) of2-amino-6-(m-chlorophenyl)-4-pyrimidinol.

EXAMPLE 14 2-Amino-6-(o-methoxyphenyl)-4-pyrimidinol

Following the procedure of Example 12 but substituting 5.67 g. (31.5 mM)of guanidine carbonate, 200 ml. of absolute ethanol, 20 ml. of toluene,14.15 g. of ethyl-o-methoxybenzoyl acetate, and 150 hours of refluxgives 7.91 g. (57.8%) of 2-amino-6-(o-methoxyphenyl)-4-pyrimidinol as awhite solid (m.p. 283.5°-284.5° C.)

EXAMPLE 15 2-Amino-5-bromo-6-(m-chlorophenyl)-4-pyrimidinol

To 3.13 g. (15 mM) of 2-amino-6-(m-chlorophenyl)-4-pyrimidinol is added80 ml. of glacial acetic acid. The solution is heated to 80° C. and 0.81ml. of Br₂ is added. The mixture is allowed to stir at 80° C. for 15minutes and cooled to 25° C. The mixture is evaporated to dryness undervacuum at 40° C. and the resulting solids heated at reflux with 150 ml.of water. The reaction mixture is cooled and filtered, and the solidswashed very well with cold water. The solids are dried at 60° C. in avacuum oven and pulverized when dry. The boiling water tritration isrepeated. 3.90 G. (86.9%) of title compound is recovered.Recrystallization of the solids from water:DMF by adding DMF slowly to astirring slurry of 3.9 g. of compound in 150 ml. boiling water untilsolution occurs, cooling and filtering yields analytically pure material(80% recovery).

EXAMPLE 16 2-Amino-6-(m-chlorophenyl)-5-iodo-4-pyrimidinol

To 3.13 g. (15 mM) of 2-amino-6-(m-chlorophenyl)-4-pyrimidinol is added50 ml. water+0.80 g. sodium hydroxide (20 mM). The mixture is heatead todissolve the pyrimidinol and filtered if necessary. It is cooled to 25°C. and 3.79 g. of I₂ (powdered) is added in 100 ml. chloroform. Theexcess I₂ is washed in with 30 ml. chloroform. The reaction mixture isallowed to stir vigorously with paddle stirrer at 25° C. for 4 hours.

The reaction is filtered and the solids washed very well with wateruntil the aqueous wash is neutral to litmus. The solids are then washedwith acetone until the acetone wash is colorless. (It is desirable topulverize the solids before washing with acetone). Drying the solids at60° C. yields 3.50 g. (67%) of 2-amino-6-(m-chlorophenyl)-4-pyrimidinol.

EXAMPLE 17 2-Amino-5-iodo-6-(2-furyl)-4-pyrimidinol

To 2.65 g. (15 mM) of 2-amino-6-(2-furyl-4-pyrimidinol is added 50 ml.water and 0.72 g. sodium hydroxide. The reaction mixture is heated to75° C. to effect solution and then cooled to 25° C. A slurry of 4.0 g.(15.8 mM) of powdered iodine in 100 ml. chloroform is added, withvigorous stirring, and the reaction mixture is allowed to stir for 2hours at ambient temperature. The reaction mixture is filtered. Thesolids are washed well with water (until wash is neutral to litmus)followed by acetone (until the acetone wash is colorless), and dried ina vacuum oven to give 3.95 g. (87%) of2-amino-5-iodo-6-(2-furyl)-4-pyrimidinol.

EXAMPLE 18 2-Amino-5-bromo-6-(2-furyl)-4-pyrimidinol

To 2.65 g. (15 mM) of 2-amino-6-(2-furyl)-4-pyrimidinol is added 50.0ml. of water and 0.66 sodium hydroxide (16.5 mM). A cloudy solutionresults. The solution is allowed to stir for 30 minutes and 0.9 ml. Br₂(2.62 g., 16.5 mM) in 20 ml. chloroform is added. The solution isallowed to stir vigorously for 2 hours and is filtered. The solids arewashed well with water (until neutral to litmus) followed by acetone(until acetone is colorless) and dried at 60° C. to give 3.3 g. of2-amino-5-bromo-6-(2-furyl)-4-pyrimidinol (86%).

EXAMPLE 19 2-Amino-5-chloro-6-phenyl-4-pyrimidinol

To 1.87 g. (10 mM) of 2-amino-6-phenyl-4-pyrimidinol is added 50 ml. ofglacial acetic acid and 1.46 g. (11 mM) of N-chlorosuccinimide. Themixture is heated with magnetic stirring under nitrogen at 90° C. for 2hours (solution was complete in less than 20 minutes). The heat isremoved and the amber solution is allowed to cool to room temperature.The solution is evaporated to a volume of 10 ml. under vacuum, cooled to20° C. and filtered. The resulting solids are washed successively withCH₃ COOH (5 ml.), water (50 ml.), acetone (100 ml.) and diethyl ether(100 ml.). The solids are dried at 60° C. in a vacuum oven to yield 1.40g. (63%) of title compound. The solids can be recrystallized fromethanol:DMF by adding DMF to a hot, ethanol slurry of the pyrimidineuntil solution is complete. Cooling the solution at 5° C. for 18 hoursfiltering and drying gives analytically pure2-amino-5-chloro-6-phenyl-4-pyrimidinol.

EXAMPLE 20 2-Amino-5-iodo-6-phenyl-4-pyrimidinol

Following the procedure of Example 16 but substituting 21.4 g. (0.113M)of 2-amino-6-phenyl-4-pyrimidinol, 200 ml. water, 500 ml. chloroform,5.6 g. sodium hydroxide and 28.8 g. I₂, a yield of 29.0 g. (78%) of2-amino-5-iodo-6-phenyl-4-pyrimidinol is obtained.

EXAMPLE 21 2-Amino-5-iodo-6-phenyl-4-pyrimidinol, zinc salt

To 1.56 g. (5 mmole) of 2-amino-5-iodo-6-phenyl-4-pyrimidinol in 15 ml.of methanol under nitrogen with stirring at room temperature is added1.1 ml. of a 25% NaOCH₃ /CH₃ OH solution. After five minutes 340 mg.(2.5 mmole) of anhydrous zinc chloride (ZnCl₂)) was added. After onehour the heterogeneous solution is concentrated to dryness, washed with2×50 ml. water, filtered, and dried in vacuo at 60° C. for 18 hours. Theproduce is a white solid with m.p. at 285° C.

The present invention comprises the administration of a compound of theformula: ##STR20## wherein X₃ is equal to X, X₄, or X₅ wherein X₄ isfluoro, chloro, bromo or iodo, and X₅ is mono-, di- or trihalomethyl,mono-, di- or trifluoroethyl, perfluoropropyl, and wherein X is alkyl offrom 1 to 3 carbon atoms, inclusive, 2-propynyl and 2-propenyl, and X₁is a member selected from the group consisting of

(a) phenyl,

(b) a monosubstituted phenyl of the formula: ##STR21## wherein one ofthe groups R, R₁, R₂, R₃, R₄ is not hydrogen and wherein R or R₄ isalkyl of from 1 to 8 carbon atoms, inclusive, alkoxy of from 1 to 8carbon atoms, fluoro, chloro, bromo, iodo or nitro; R₁ or R₃ is fluoro,chloro, bromo, iodo, nitro; trifluoromethyl or alkoxy of from 1 to 8carbon atoms, alkoxyethyloxy wherein alkoxy is from 1 to 3 carbon atoms,inclusive, or ##STR22## wherein R₅ and R₆ are the same or different andare alkyl of from 1 to 8 carbon atoms, inclusive, benzyl, or takentogether with --N> are a saturated cycloalkylamino group ##STR23##wherein n' is 3, 4, 5 or 6 or dialkyl substituted cycloalkylaminowherein each alkyl is from 1 to 3 carbon atoms, inclusive; and R₂ ischloro, fluoro, bromo, iodo, or alkyl of from 1 to 5 carbon atoms,inclusive;

(c) a disubstituted phenyl of the formula: ##STR24## wherein any two ofR, R₁, R₂, R₃ and R₄ are not hydrogen and are the same or different andare fluoro, chloro, bromo, iodo, alkyl of from 1 to 8 carbon atoms,alkoxy of from 1 to 8 carbon atoms, nitro and trifluoromethyl;

(d) a trihalo substituted phenyl wherein halo is chloro, bromo, iodo, orfluoro;

(e) α-naphthyl of the formula: ##STR25## wherein R₇ is substituted ineither ring and is hydrogen, alkyl of from 1 to 8 carbon atoms,inclusive, including isomeric forms, alkoxy of from 1 to 8 carbon atoms,inclusive, including isomeric forms, fluoro, chloro, iodo, bromo ornitro;

(f) 2-furyl,

(g) 3-pyridyl,

(h) 2-pyridyl and

(i) 2-pyrazyl,

or a salt thereof in association with a pharmaceutical carrier to ahuman or animal.

Suitable pharmacologically acceptable acid addition salts are forexample the hydrochloride, sulfate, phosphate, nitrate, and the like.These salts can be used in the same manner as the base compounds.

According to the present invention, the immunoregulatory system isaltered by administering the active ingredients to a suitable host. By"host" is meant animals, i.e., intact viable animals. The host may bewarm-blooded animals such as mammals, e.g., mice, rats, rabbits,bovines, pigs, hamsters, dogs, cats, guinea pigs, horses, goats, sheep,monkeys, man; and birds, e.g., chickens, ducks, turkeys, pigeons,parakeets, and canaries. The mode of administration can be parenterallysuch as subcutaneously, intramuscularly, intradermally,intraperitoneally, intrathecally, intravenously or locally, on a mucousmembrane such as intranasally, pharyngolaryngeally, bronchially,broncholially, intravaginally, rectally or ocularly. The mode ofadministration can also be by implantation. Alternatively orconcurrently, administration can be by the oral route, a preferred modeof administration. Practically, it is advantageous to administer theactive ingredient to the host orally, intranasally, topically, locally,subcutaneously or intramuscularly.

Preferred compounds are:

2-amino-5-iodo-6-(3-bromophenyl)-4-pyrimidinol;

2-amino-5-bromo-6-(3-fluorophenyl)-4-pyrimidinol;

2-amino-5-bromo-6-(3-ethoxyethylphenyl)-4-pyrimidinol;

2-amino-5-bromo-6-(2-methoxyphenyl)-4-pyrimidinol;

2-amino-5-chloro-6-(2-methoxyphenyl)-4-pyrimidinol;

2-amino-5-iodo-6-(2-methoxyphenyl)-4-pyrimidinol;

2-amino-5-bromo-6-(3-chlorophenyl)-4-pyrimidinol;

2-amino-5-iodo-6-(3-chlorophenyl)-4-pyrimidinol;

2-amino-5-chloro-6-(3-chlorophenyl)-4-pyrimidinol;

2-amino-5-chloro-6-(2-fluorophenyl)-4-pyrimidinol;

2-amino-5-chloro-6-(3-fluorophenyl)-4-pyrimidinol;

2-amino-5-bromo-6-(2-fluorophenyl)-4-pyrimidinol;

2-amino-5-iodo-6-(3-fluorophenyl)-4-pyrimidinol;

2-amino-5-iodo-6-phenyl-4-pyrimidinol;

2-amino-5-chloro-6-phenyl-4-pyrimidinol;

2-amino-5-bromo-6-phenyl-4-pyrimidinol;

2-amino-5-chloro-6-(3-methoxyphenyl)-4-pyrimidinol;

2-amino-5-bromo-6-(3-methoxyphenyl)-4-pyrimidinol;

2-amino-5-iodo-6-(3-methoxyphenyl)-4-pyrimidinol;

2-amino-5-bromo-6-(2-pyridyl)-4-pyrimidinol;

2-amino-5-iodo-6-(3,4-dichlorophenyl)-4-pyrimidinol;

2-amino-5-bromo-6-(α-naphthyl)-4-pyrimidinol;

2-amino-5-chloro-6-(3-nitrophenyl)-4-pyrimidinol;

2-amino-5-iodo-6-(3-nitrophenyl)-4-pyrimidinol;

2-amino-5-iodo-6-(3-trifluoromethylphenyl)-4-pyrimidinol;

2-amino-5-ethyl-6-phenyl-4-pyrimidinol;

2-amino-5-bromo-6-(3,5-dimethoxyphenyl)-4-pyrimidinol;

2-amino-5-chloro-6-(3-propyloxyphenyl)-4-pyrimidinol;

or the pharmaceutically acceptable acid addition salts or alkali metalor alkaline earth metal salts thereof.

The method of the present invention is for alteration of theimmunoregulatory system of the host animal. The administration of theactive compounds increases antibody formation and can be used to treatacquired or congenital hypogammaglobulinemia; activates macrophages andcan be used to treat or prevent intracellular or extraceullar parasiticinfections, including bacterial and protozoal; increases hematopoieticstem cells in bone marrow and spleen and can be used to treat or preventaplastic anemia; and decreases generation of allospecific killer cellsand can be used to prevent rejection of organ and skin grafts.

The dosage administered will be dependent upon the the type of animalinvolved, its age, health, weight, kind of concurrent treatment, if any,frequency of treatment, therapeutic ratio, and tolerance.

Illustratively, dosage levels of the administered active ingredients canbe: intravenous, 0.1 to about 100 mg./kg.; intraperitoneal, 0.1 to about100 mg./kg.; subcutaneous, 0.1 to about 150 mg./kg.; intramuscular, 0.1to about 150 mg./kg.; orally, 0.1 to about 400 mg./kg., and preferablyabout 1 to 10 mg./kg.; intranasal instillation, 0.1 to about 50 mg./kg.;and aerosol, 0.1 to about 50 mg./kg. of animal (body) weight.

Expressed in terms of concentration, an active ingredient can be presentin the compositions of the present invention for localized use about thecutis, intranasally, pharyngolaryngeally, bronchially, broncholially,intravaginally, rectally, or ocularly in a concentration of from about0.1 to about 50% w/w of the composition; preferably about 1 to about 20%w/w of the composition; and for parenteral use in a concentration offrom about 0.5 to about 50% w/v of the composition and preferably fromabout 5 to about 20% w/v.

The compositions of the present invention are preferably presented foradministration to humans and animals in unit dosage forms, such astablets, capsules, pills, powders, granules, suppositories, sterileparenteral solutions or suspensions, sterile non-parenteral solutions orsuspensions, and oral solutions or suspensions and the like, containingsuitable quantities of an active ingredient.

For oral administration either solid or fluid unit dosage forms can beprepared.

Powders are prepared quite simply by comminuting the active ingredientto a suitably fine size and mixing with a similarly comminuted diluent.The diluent can be an edible carbohydrate material such as lactose orstarch. Advantageously, a sweetening agent or sugar is present as wellas a flavoring oil.

Capsules are produced by preparing a powder mixture as hereinbeforedescribed and filling into formed gelatin sheaths. Advantageously, as anadjuvant to the filling operation, a lubricant such as talc, magnesiumstearate, calcium stearate and the like is added to the powder mixturebefore the filling operation.

Soft gelatin capsules are prepared by machine encapsulation of a slurryof active ingredients with an acceptable vegetable oil, light liquidpetrolatum or other inert oil or triglyceride.

Tablets are made by preparing a powder mixture, granulating or slugging,adding a lubricant and pressing into tablets. The powder mixture isprepared by mixing an active ingredient, suitably comminuted, with adiluent or base such as starch, lactose, kaolin, dicalcium phosphate andthe like. The powder mixture can be granulated by wetting with a bindersuch as corn syrup, gelating solution, methylcellulose solution oracacia mucilage and forcing through a screen. As an alternative togranulating, the powder mixture can be slugged, i.e., run through thetablet machine and the resulting imperfectly formed tablets broken intopieces (slugs). The slugs can be lubricated to prevent sticking to thetablet-forming dies by means of the addition of stearic acid, a stearicsalt, talc or mineral oil. The lubricated mixture is then compressedinto tablets.

Advantageously the tablet can be provided with a protective coatingconsisting of a sealing coat or enteric coat of shellac, a coating ofsugar and methylcellulose and a polish coating of carnauba wax.

Fluid unit dosage forms for oral administration such as syrups, elixirsand suspensions can be prepared wherein each teaspoonful of compositioncontains a predetermined amount of active ingredient for administration.The water-soluble forms can be dissolved in an aqueous vehicle togetherwith sugar, flavoring agents and preservatives to form a syrup. Anelixir is prepared by using a hydroalcoholic vehicle with suitablesweeteners together with a flavoring agent. Suspensions can be preparedof the insoluble forms with a suitable vehicle with the aid of asuspending agent such as acacia, tragacanth, methylcellulose and thelike.

For parenteral administration, fluid unit dosage forms are preparedutilizing an active ingredient and a sterile vehicle, water beingpreferred. The active ingredient, depending on the form andconcentration used, can be either suspended or dissolved in the vehicle.In preparing solutions the water-soluble active ingredient can bedissolved in water for injection and filter sterilized before fillinginto a suitable vial or ampule and sealing. Advantageously, adjuvantssuch as a local anesthetic, preservative and buffering agents can bedissolved in the vehicle. Parenteral suspensions are prepared insubstantially the same manner except that an active ingredient issuspended in the vehicle instead of being dissolved and sterilizationcannot be accomplished by filtration. The active ingredient can besterilized by exposure to ethylene oxide before suspending in thesterile vehicle. Advantageously, a surfactant or wetting agent isincluded in the composition to facilitate uniform distribution of theactive ingredient.

In addition to oral and parenteral administration, the rectal andvaginal routes can be utilized. An active ingredient can be administeredby means of a suppository. A vehicle which has a melting point at aboutbody temperature or one that is readily soluble can be utilized. Forexample cocoa butter and various polyethylene glycols (Carbowaxes) canserve as the vehicle.

For intranasal instillation, fluid unit dosage forms are preparedutilizing an active ingredient and a suitable pharmaceutical vehicle,water being preferred or by dry powder for insufflation.

The active ingredients can also be admixed in animal feed. The activeingredients can conveniently be prepared in the form of a food premix.The food premix can comprise an active ingredient in admixture with anedible pharmaceutical diluent such as starch, oatmeal, flour, calciumcarbonate, talc, dried fish meal and the like nontoxic, orallyacceptable pharmaceutical diluents. The prepared premix is thenconveniently added to the regular feed.

For use as aerosols the active ingredients can be packaged in apressurized aerosol container together with a gaseous or liquefiedpropellant, for example, dichlorodifluoromethane, carbon dioxide,nitrogen, propane, and the like, with the usual adjuvants such asco-solvents and wetting agents, as may be necessary or desirable.

The term "unit dosage form" as used in the specification and claimsrefers to physically discrete units suitable as unitary dosages forhuman and animal subjects, each unit containing a predetermined quantityof active material calculated to produce the desired therapeutic effectin association with the required pharmaceutical diluent, carrier orvehicle. The specifications for the novel unit dosage forms of thisinvention are dictated by and are directly dependent on (a) the uniquecharacteristics of the active material and the particular therapeuticeffect to be achieved, and (b) the limitation inherent in the art ofcompounding such an active material for therapeutic use in humans, asdisclosed in this specification, these being features of the presentinvention. Examples of suitable unit dosage forms in accord with thisinvention are tablets, capsules, troches, suppositories, powder packets,wafers, cachets, teaspoonfuls, tablespoonfuls, dropperfuls, ampuls,vials, segregated multiples of any of the foregoing, and other forms asherein described.

The active ingredients to be employed for immunoregulation can be easilyprepared in unit dosage form with the employment of pharmaceuticalmaterials which themselves are available in the art and can be preparedby established procedures. The following preparations are illustrativeof the preparation of the unit dosage forms of the present invention,but are not intended to be limiting.

EXAMPLE 22 Hard-Gelatin Capsules

One thousand two-piece hard gelatin capsules for oral use, each capsulecontaining 100 mg. of 2-amino-5-bromo-6-phenyl-4(1H)-pyrimidinone, areprepared from the following types and amounts of ingredients:

2-Amino-5-bromo-6-phenyl-4(1H)-pyrimidinone, micronized: 100 gm.

Lactose: 100 gm.

Corn starch: 20 gm.

Talc: 20 gm.

Magnesium stearate: 2 gm.

The 2-amino-5-bromo-6-phenyl-4(1H)-pyrimidinone, finely divided by meansof an air micronizer, is added to the other finely powdered ingredients,mixed thoroughly and then encapsulated in the usual manner.

The foregoing capsules are useful for preventing or treating skin graftrejection by the oral administration of one or two capsules one to fourtimes a day.

Using the procedure above, capsules are similarly prepared containing2-amino-5-bromo-6-phenyl-4(1H)-pyrimidinone in 50, 250 and 500 mg.amounts by substituting 50 gm., 250 gm. and 500 gm. of2-amino-5-bromo-6-phenyl-4(1H)-pyrimidinone for the 100 gm. used above.

EXAMPLE 23 Soft Gelatin Capsules

One-piece soft gelatin capsules for oral use, each containing 250 mg. of2-amino-5-bromo-6-phenyl-4(1H)-pyrimidinone (finely divided by means ofan air micronizer), are prepared by first suspending the compound in 0.5ml. of corn oil to render the material capsulatable and then capsulatingin the above manner.

The foregoing capsules are useful for preventing or treating bacterialinfection particularly intracellular bacterial infection by the oraladministration of one or two capsules one to four times a day.

EXAMPLE 24 Tablets

One thousand tablets, each containing 500 mg. of2-amino-5-bromo-6-phenyl-4(1H)-pyrimidinone, are prepared from thefollowing types and amounts of ingredients:

2-Amino-5-bromo-6-phenyl-4(1H)-pyrimidinone: 500 gm.

Lactose: 75 gm.

Corn starch: 50 gm.

Magnesium stearate: 4 gm.

Light liquid petrolatum micronized: 5 gm.

The 2-amino-5-bromo-6-phenyl-4(1H)-pyrimidinone, finely divided by meansof an air micronizer, is added to the other ingredients and thenthoroughly mixed and slugged. The slugs are broken down by forcingthrough a Number Sixteen screen. The resulting granules are thencompressed into tablets, each tablet containing 500 mg. of2-amino-5-bromo-6-phenyl-4(1H)-pyrimidinone.

The foregoing tablets are useful for treating hypogammaglobulinemia bythe oral administration of one or two tablets one to four times a day.

Using the procedure above, tablets are similarly prepared containing2-amino-5-bromo-6-phenyl-4(1H)-pyrimidinone in 250 mg. and 100 mg.amounts by substituting 250 gm. and 10 gm. of2-amino-5-bromo-6-phenyl-4(1H)-pyrimidinone for the 500 gm. used above.

EXAMPLE 25 Oral Suspension

One thousand ml. of an aqueous suspension for oral use, containing ineach teaspoonful (5 ml.) dose, 500 mg. of2-amino-5-bromo-6-phenyl-4(1H)-pyrimidinone, is prepared from thefollowing types and amounts of ingredients:

2-Amino-5-bromo-6-phenyl-4(1H)-pyrimidinone, micronized: 100 gm.

Citric acid: 2 gm.

Benzoic acid: 1 gm.

Sucrose: 700 gm.

Tragacanth: 5 gm.

Lemon oil: 2 gm.

Deionized water, q.s. 1000 ml.

The citric acid, benzoic acid, sucrose, tragacanth and lemon oil aredispersed in sufficient water to make 850 ml. of suspension. The2-amino-5-bromo-6-phenyl-4(1H)-pyrimidinone, finely divided by means ofan air micronizer, is stirred into the syrup until uniformlydistributed. Sufficient water is added to make 1000 ml.

The composition so prepared is useful for treating aplastic anemia at adose of 1 tablespoonful (15 ml.) three times a day.

EXAMPLE 26

A sterile aqueous suspension for parenteral injection, containing in 1ml. 300 mg. of 2-amino-5-iodo-6-phenyl-4(1H)-pyrimidinone, is preparedfrom the following types and amounts of ingredients:

2-Amino-5-iodo-6-phenyl-4(1H)-pyrimidinone, micronized: 300 gm.

Polysorbate 80: 5 gm.

Methylparaben: 2.5 gm.

Propylparaben: 0.17 gm.

Water for injection, q.s. 1000 ml.

All the ingredients, except the2-amino-5-iodo-6-phenyl-4(1H)-pyrimidinone, are dissolved in the waterand the solution sterilized by filtration. To the sterile solution isadded the sterilized 2-amino-5-iodo-6-phenyl-4(1H)-pyrimidinone, finelydivided by means of an air micronizer, and the final suspension isfilled into sterile vials and the vials sealed.

The composition so prepared is useful for treating agammaglobinemia at adose of 1 milliliter (IM) three times a day.

EXAMPLE 27 Suppository, Rectal and Vaginal

One thousand suppositories, each weighing 2.5 gm. and containing 150 mg.of 2-amino-5-bromo-6-phenyl-4(1H)-pyrimidinone are prepared from thefollowing types and amounts of ingredients:

2-Amino-5-bromo-6-phenyl-4(1H)-pyrimidinone, micronized: 150 gm.

Propylene glycol: 150 gm.

Polyethylene glycol, 4000 q.s.: 2,500 gm.

The 2-amino-5-bromo-6-phenyl-4(1H)-pyrimidinone is finely divided bymeans of an air micronizer and added to the propylene glycol and themixture passed through a colloid mill until uniformly dispersed. Thepolyethylene glycol 40000 is melted and the propylene glycol dispersionadded slowly with stirring. The suspension is poured into unchilledmolds at 40° C. The composition is allowed to cool and solidify and thenremoved from the mold and each suppository foil wrapped.

The foregoing suppositories are inserted rectally or vaginally fortreating bacterial infection.

EXAMPLE 28 Intranasal Suspension

One thousand ml. of a sterile aqueous suspension for intranasalinstillation, containing in each ml. 150 mg. of2-amino-5-bromo-6-phenyl-4(1H)-pyrimidinone, is prepared from thefollowing types and amounts of ingredients.

2-Amino-5-bromo-6-phenyl-4(1H)-pyrimidinone, micronized: 150 gm.

Polysorbate 80: 5 gm.

Methylparaben: 2.5 gm.

Propylparaben: 0.17 gm.

Deionized water, q.s. 1000 ml.

All the ingredients, except the2-amino-5-bromo-6-phenyl-4(1H)-pyrimidinone, are dissolved in the waterand the solution sterilized by filtration. To the sterile solution isadded the sterilized 2-amino-5-bromo-6-phenyl-4(1H)-pyrimidinone, finelydivided by means of an air micronizer, and the final suspension isaseptically filled into sterile containers.

The composition so prepared is useful for treating intracellularbacterial infection by intranasal instillation of 0.2 to 0.5 ml. givenone to four times per day.

EXAMPLE 29 Animal Feed

One thousand grams of feed premix is prepared from the following typesand amounts of ingredients:

2-Amino-5-bromo-6-phenyl-4(1H)-pyrimidinone: 20 gm.

Soybean meal: 400 gm.

Fish meal: 400 gm.

Wheat germ oil: 50 gm.

Sorghum molasses: 130 gm.

The ingredients are mixed together and pressed into pellets.

The premix can be fed to laboratory animals directly, i.e., rats andmice, for preventing or treating intracellular parasitic infection.

For larger animals the premix can be added to the animal's regular feedin an amount calculated to give the desired dose of2-amino-5-bromo-6-phenyl-4(1H)-pyrimidinone. For example, one part ofpremix is added to 2.5 parts of a cat's regular feed to provide thedesired dose of 200 mg./kg./day for a cat of 2.5 kg.

An active ingredient can also be present, as shown in Examples 30-33 inthe undiluted pure form for use locally about the cutis, intranasally,pharyngolaryngeally, bronchially, broncholially or orally.

EXAMPLE 30 Oral Powder

One thousand grams of 2-amino-5-bromo-6-phenyl-4(1H)-pyrimidinone inbulk form is finely divided by means of an air micronizer. Themicronized powder is divided into individual doses of 250 mg. andpackaged.

The foregoing powders are useful for preventing or treating protozoalinfection by the oral administration of one or two powders suspended ina glass of water, one to four times per day.

EXAMPLE 31 Hard Gelatin Capsules

One thousand two-piece hard gelatin capsules for oral use, each capsulecontaining 100 mg. of 2-amino-5-bromo-6-phenyl-4(1H)-pyrimidinone, areprepared from 100 grams of 2-amino-5-bromo-6-phenyl-4(1H)-pyrimidinone.

The 2-amino-5-bromo-6-phenyl-4(1H)-pyrimidinone is finely divided bymeans of an air micronizer and encapsulated in the usual manner.

Using the procedure above, capsules are similarly prepared containing2-amino-5-bromo-6-phenyl-4(1H)-pyrimidinone in 50, 250 and 500 mg.amounts by substituting 50 gm., 250 gm. and 500 gm. of2-amino-5-bromo-6-phenyl-4(1H)-pyrimidinone for the 100 gm. used above.

EXAMPLE 32

Following the procedure of the preceding Examples 22 through 31,inclusive, compositions are prepared substituting equivalent amounts ofthe pharmaceutically acceptable acid addition salts of2-amino-5-bromo-6-phenyl-4(1H)-pyrimidinone for the free base of theexamples.

EXAMPLE 33

Following the procedure of the preceding Examples 22 through 31,inclusive, compositions are prepared substituting equivalent amounts of

2-amino-5-iodo-6-(3-bromophenyl)-4-pyrimidinol;

2-amino-5-bromo-6-(3-fluorophenyl)-4-pyrimidinol;

2-amino-5-bromo-6-(3-ethoxyethylphenyl)-4-pyrimidinol;

2-amino-5-bromo-6-(2-methoxyphenyl)-4-pyrimidinol;

2-amino-5-chloro-6-(2-methoxyphenyl)-4-pyrimidinol;

2-amino-5-iodo-6-(2-methoxyphenyl)-4-pyrimidinol;

2-amino-5-bromo-6-(3-chlorophenyl)-4-pyrimidinol;

2-amino-5-iodo-6-(3-chlorophenyl)-4-pyrimidinol;

2-amino-5-chloro-6-(3-chlorophenyl)-4-pyrimidinol;

2-amino-5-chloro-6-(2-fluorophenyl)-4-pyrimidinol;

2-amino-5-chloro-6-(3-fluorophenyl)-4-pyrimidinol;

2-amino-5-bromo-6-(2-fluorophenyl)-4-pyrimidinol;

2-amino-5-iodo-6-(3-fluorophenyl)-4-pyrimidinol;

2-amino-5-iodo-6-phenyl-4-pyrimidinol;

2-amino-5-chloro-6-phenyl-4-pyrimidinol;

2-amino-5-bromo-6-phenyl-4-pyrimidinol;

2-amino-5-chloro-6-(3-methoxyphenyl)-4-pyrimidinol;

2-amino-5-bromo-6-(3-methoxyphenyl)-4-pyrimidinol;

2-amino-5-iodo-6-(3-methoxyphenyl)-4-pyrimidinol;

2-amino-5-bromo-6-(2-pyridyl)-4-pyrimidinol;

2-amino-5-iodo-6-(3,4-dichlorophenyl)-4-pyrimidinol;

2-amino-5-bromo-6-(α-naphthyl)-4-pyrimidinol;

2-amino-5-chloro-6-(3-nitrophenyl)-4-pyrimidinol;

2-amino-5-iodo-6-(3-nitrophenyl)-4-pyrimidinol;

2-amino-5-iodo-6-(3-trifluoromethylphenyl)-4-pyrimidinol;

2-amino-5-ethyl-6-phenyl-4-pyrimidinol;

2-amino-5-bromo-6-(3,5-dimethoxyphenyl)-4-pyrimidinol;

2-amino-5-chloro-6-(3-propyloxyphenyl)-4-pyrimidinol;

or the pharmaceutically acceptable acid addition salts or the alkalimetal or alkaline earth metal salts of each of the foregoing compoundsfor active ingredients of each of the examples. Those compositions areuseful as immune modulators. as described above and in Examples 22through 31, inclusive.

We claim:
 1. A process for treating aplastic anemia comprising thesystemic administration of an effective amount for treating aplasticanemia of a compound of the formula: ##STR26## wherein X₃ is equal to X,X₄, or X₅ wherein X₄ is fluoro, chloro, bromo or iodo, and X₅ is mono-,di- or trihalo methyl, mono-, di- or trifluoroethyl, perfluoropropyl andX is alkyl of from 1 to 3 carbon atoms, inclusive, 2-propynyl,2-propenyl, and alkyloxyacyl where alkyl is as defined above, and X₁ isa member selected from the group consisting of:(a) phenyl, (b) amonosubstituted phenyl of the formula: ##STR27## wherein provided thatonly one of groups R, R₁, R₂, R₃, R₄ is other than hydrogen and R or R₄is alkyl of from 1 to 8 carbon atoms, inclusive, including isomericforms, alkoxy of from 1 to 8 carbon atoms, inclusive, including isomericforms, fluoro, chloro, bromo, iodo, or nitro; R₁ or R₃ is fluoro,chloro, bromo, iodo, nitro, trifluoromethyl or alkoxy of from one toeight carbon atoms, alkoxyethyloxy wherein alkoxy is from 1 to 5 carbonatoms, inclusive, or ##STR28## wherein R₅ and R₆ are the same ordifferent and are alkyl of from 1 to 8 carbon atoms, inclusive, benzylor taken together with --N< are a saturated cycloalkylamino group##STR29## wherein n' is 3, 4, 5 or 6 or dialkyl substitutedcycloalkylamino wherein each alkyl is from 1 to 3 carbon atoms,inclusive; and R₂ is chloro, fluoro, bromo, iodo, or alkyl of from 1 to3 carbon atoms, inclusive, (c) a disubstituted phenyl of the formula:##STR30## wherein any two of R, R₁, R₂, R₃ and R₄ are not hydrogen andare the same or different and are fluoro, chloro, bromo, iodo, alkyl offrom 1 to 8 carbon atoms, including isomeric forms, alkoxy of from 1 to8 carbon atoms, inclusive isomeric forms, nitro and trifluoromethyl; (d)a trihalo substituted phenyl wherein halo is chloro, bromo, iodo orfluoro, (e) α-naphthyl of the formula: ##STR31## wherein R issubstituted in either ring and is hydrogen, alkyl of from 1 to 8 carbonatoms, inclusive, including isomeric forms, alkoxy of from 1 to 8 carbonatoms, inclusive, including isomeric forms, fluoro, chloro, iodo, bromoor nitro, (f) 2-furyl, (g) 3-pyridyl, (h) 2-pyridyl and (i) 2-pyrazyl,ora salt thereof in association with a pharmaceutical carrier to a humanor animal having aplastic anemia.
 2. The process of claim 1 wherein theamount of compound administered is from about 0.1 to about 10 mg/kg ofbody weight of the human or animal.
 3. The process of claim 2 whereinthe compound administered is2-amino-5-bromo-6-phenyl-4(1H)-pyrimidinone.
 4. The process of claim 2wherein the compound administered is2-amino-5-iodo-6-phenyl-4(1H)-pyrimidinone.